Sovateltide prevents beta‐amyloid plaque load and restores memory deficit in an APP/PS1 mouse model of Alzheimer's disease

Abstract

AbstractBackgroundEndothelin B (ETB) receptor agonist, sovateltide, is being investigated as a potential therapeutic agent for AD. However, its causative effects on decreasing beta‐amyloid (Aβ) plaque load and rescuing impaired memory in APP/PS1 mice remain unclear. In the present study, we have examined the effects of SOVA on Aβ plaques formation and functional recovery in transgenic AD mice and explored its mechanism(s) of action.MethodAPP/PS1 transgenic mice and C57BL/6 control mice were divided into two groups (vehicle and sovateltide). Sovateltide (5 μg/kg) was intravenously injected three times at 2‐hour intervals on days 1, 3, and 6 every month until study endpoints (3, 6, and 12 months age). Memory deficit was assessed using the Morris water maze test. Separate sets of mice were sacrificed at the end of 3, 6, and 12 months and Aβ plaque formation was examined in the brain. Mitochondrial dysfunction, neurogenesis, and synaptogenesis were assessed using western blot and immunofluorescence techniques.ResultAPP/PS1 transgenic mice showed significant (p<0.001) impairment in spatial memory. Treatment with SOVA rescued learning deficits and relieved memory retention in APP/PS1 mice. SOVA treatment significantly reduced memory deficit in 6 months (40%) and 12 months (46%) aged transgenic mice. SOVA administration also significantly (p<0.001) decreased Aβ plaque load in the brain compared to vehicle. Moreover, SOVA attenuated neuronal loss in the hippocampus and enhanced neurogenesis in APP/PS1 mice as evident by increased expression of NeuroD1 (p<0.0001), DoubleCortin (p<0.0001), and NeuN (p<0.0001) along with an upregulation of synaptic proteins (synapsin‐1, synaptophysin, and postsynaptic density‐95) compared to vehicle at 6 and 12 months. Further study demonstrated that treatment with SOVA upregulated (p<0.0001) mitochondrial fusion proteins, Mfn1, Mfn2, Opa1, and downregulated fission proteins, Drp1 and Fis1, compared to vehicle at 6 and 12 months. There were no changes in the expression of any of these markers at three months.ConclusionSOVA can improve functional recovery and has a neuroprotective effect in APP/PS1 mice via triggering neurogenesis and improving mitochondrial function mediated by ETB receptor signaling pathway, which could help in improving neurological deficits. Therefore, SOVA has the potential to be developed as a novel drug for the treatment of AD.